Prostate cancer is the most common solid tumor affecting American adult males. While the disease course is well-understood, there are significant opportunities to improve non-invasive molecular imaging in prostate cancer diagnosis, staging, therapy and management. At present there is no specific radiotracer used for positron emission tomography (PET) - the most sensitive molecular imaging modality. Despite extensive experience in prostate cancer radioimmunotherapy (RIT) clinical trials at Weill Cornell Medical Center based on a humanized monoclonal antibody (huJ591), data analysis has been limited by the lack of quantitative imaging. It is only now possible to combine PET sensitivity with mAb specificity (Immuno- PET) in the clinic. We therefore propose to develop Immuno-PET using J591 mAb and 89Zr - an ideal positron (2+) emitter with physical characteristics necessary for antibody imaging - halflife (3.27 days) and positron energy (Emean = 0.395 MeV). Specifically, this research proposal will test the hypothesis that Immuno-PET based on anti-PSMA (prostate specific membrane antigen) mAb, 89Zr-J591 can enhance specificity, assess tumor progression, and monitor the relative efficacy of current Phase II and III clinical RIT trials. Preclinical studies have been designed using PSMA-positive LNCaP human cell line and non-human RM1.PGLS cell lines to measure specific 89Zr-J591 antigen targeting, internalization and biodistribution in tumor-bearing mice. The results of these studies will be compared and contrasted with another investigational radiopharmaceutical 18F labeled MIP-1224, a PSMA inhibitor. MicroPET non-invasive imaging and biodistribution studies will further determine pharmacokinetics and tumor uptake of these two tracers. To underscore the added value of ImmunoPET in RIT trials, serial PET imaging studies will be performed following 2- radiation from 177Lu-J591 mAb in PSMA (+) xenograft and metastatic cancer models. Following 177Lu-J591 RIT, correlative anatomic imaging studies using a small animal 7 Tesla MRI scanner will be performed. The expected outcome of this study is the development of 89Zr-J591 mAb as an advanced prostate cancer- specific PET radiotracer. The results of this study will have a direct impact on current RIT trials based on anti-PSMA mAb cancer therapy as well as other ongoing prostate cancer imaging trials. The long-term goal will be to improve the specificity of metastatic prostate cancer diagnosis, selection of candidates for treatment, and accuracy of therapeutic dose. Ultimately, these changes will improve management of the large population of patients living with advanced prostate disease PUBLIC HEALTH RELEVANCE: Prostate cancer is the most common solid tumor affecting American adult males. This research proposal is designed to develop an imaging technique known as Immuno-PET (positron emission tomography) based on radiolabeled antibody known as Zirconim-89-J591, which binds to a specific protein known as PSMA on prostate cancer cells. The long term goal will be to improve the specificity of metastatic prostate cancer diagnosis, selection of candidates for treatment, and accuracy of determining therapeutic dose and response.